tbuckley/cabot-search huggingface dataset:
Abstract 3288: The use of <i>in vitro</i> assays to assess and measure gene therapy immunogenicity
Authors: Jana Schockaert, Thibaut J. Janss, Juliette Lamy, Aurélie Mazy, Ellen Boelen, Simon Lefevre, Sofie Pattijn
Journal: Cancer Research (2022)

Abstract Introducing the gene therapy product into human cells requires a vector that will deliver the gene into the cells and incorporate those genes into the gene expression mechanism in those cells. One of the issues is the induction of an unwanted immune response that can have an influence on the efficacy and potency of the treatment. Additionally, pre-existing immunity towards AAV and CRISPR can also neutralize the therapeutic effect. Comprehensive assessment of human immune responses to gene therapy candidates includes characterization of humoral and cellular immunogenicity specific for both the viral vector and the expressed transgene (protein) product before and after dose administration. In vitro assays such as dendritic cell activation and T cell proliferation assays can be used to assess this unwanted immunogenicity in an early phase. Additionally, innate assays such as dendritic cell activation assays can be used for the evaluation of potential impurities and innate response inducing contaminants. Sensitive Fluorospot assays can be used to monitor patient’ specific immunogenicity both at the T and B cell level. The advantage of the Fluorospot technology is the sensitivity to detect responses on a single cell level and measure up to 4 analytes simultaneously. For all in vitro assays, the quality and functionality of the primary cells is important to assure reproducibility and solid assay performance. Citation Format: Jana Schockaert, Thibaut J. Janss, Juliette Lamy, Aurélie Mazy, Ellen Boelen, Simon Lefevre, Sofie Pattijn. The use of in vitro assays to assess and measure gene therapy immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3288.
Abstract 2888: Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy
Authors: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Bin Cai, Aaron N. Nguyen, Songmao Zheng, Jiangchun Xu, Yan Li, Felix Du, Peter Luo
Journal: Cancer Research (2022)

Abstract Targeting CD28 for systemic T cell activation caused severe cytokine storm and multiorgan failure in an anti-CD28 antibody TGN1412 phase 1 trial. However, tumor specific CD28 targeting in a tumor associated antigen (TAA)×CD28 bispecific format, similar to the clinically validated tumor specific CD3 bispecific T-cell engagers (TCEs), offers an attractive solution to mitigate the serious safety concerns associated with systemic CD28 activation while delivering potent T-cell costimulatory signal. Our goal is to combine tumor specific bispecific TCEs targeting both CD3 and CD28, the two essential pathways in T cell activation for safe and long-lasting T cell-mediated synergistic immunotherapies. Following our success in utilizing the CD3 POWERbody™ TCE platform for tumor targeting with tight safety control, we further applied our suite of antibody technologies to develop tumor specific bispecific CD28 POWERbody TCE programs. Our NEObody™ and SAFEbody® technologies enabled us to discover and engineer species cross-reactive anti-CD28 antibodies targeting a unique and conserved epitope of CD28 as well as precision masking of the antigen binding sites for conditional activation in tumor microenvironment. The engineered tailor-made anti-CD28 arm and the tumor specific antigen targeting arm were then integrated into our proprietary bispecific platform that has robust CMC properties. Toward this end we developed multiple TAA×CD28 bispecific TCEs, including B7-H3×CD28, HER2×CD28, and TROP-2×CD28, etc., which possess fine-tuned specificity and safety profiles to minimize their on-target off-tumor toxicities and to prevent the systemic cytokine release syndrome (CRS). These TAA×CD28 bispecific POWERbodies have no superagonist activities on their own and can be activated for tumor antigen binding by the TAA arm and T cell engagement by the CD28 arm. When combined with TAA×CD3 TCEs and/or checkpoint inhibitors, they show strong synergistic T cell-mediated antitumor responses with robust safety profiles. Taken together, our tumor specific CD28 bispecific POWERbody TCEs exhibit enormous potential to fulfill the promises of safe and durable T cell-mediated immunotherapies when combined with CD3 bispecific POWERbody TCEs and/or checkpoint inhibitors. Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Bin Cai, Aaron N. Nguyen, Songmao Zheng, Jiangchun Xu, Yan Li, Felix Du, Peter Luo. Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2888.
Abstract 6033: Understanding the role of Cep55 in initiation and progression of cancers
Authors: Behnam Rashidieh, Simon M. Tria, Kum Kum Khanna
Journal: Cancer Research (2022)

Abstract CEP55 is a cancer-testis antigen, highly expressed in a wide range of solid tumors as well as chromosomally unstable cancers. CEP55 is normally silent in most adult somatic tissues except germ cells; however, its expression is induced early during cell transformation. Numerous studies using cell line xenografts have shown that CEP55 is required for the viability and survival of a diverse range of cancers in vitro and in vivo. To decipher the mechanisms by which Cep55 promotes chromosomal instability and tumorigenesis in vivo, we developed a novel knock-in transgenic mouse model that ubiquitously overexpresses Cep55 (Cep55Tg/Tg) and a conditional knockout (cKO) mouse model of Cep55 (Cep55-/-). While overexpression of Cep55 was sufficient to cause spontaneous tumorigenesis in vivo, Cep55 loss hindered tumorigenesis. When we bred adult Cep55 cKO mice with other tumor-prone models: oncogenic Kras expression (Kras G12D) and Pten tumor-suppressor loss, Cep55 loss significantly delayed tumorigenesis and prolonged survival validating it as a promising therapeutic target for diverse cancers. This reduction of tumorigenesis is concomitant with the downregulation of AKT and ERK signaling pathways, attenuation of epithelial to mesenchymal transition, and increased cytotoxic CD4/CD8 T-cell tumor infiltration. This indicates that Cep55 can impair the establishment of the adaptive immune response through modification in the tumor microenvironment and regulation of cell signaling. Mass spectrophotometry of mouse embryo fibroblasts and derived exosomes from wild-type and KO mice revealed the pathways altered by Cep55 such as extracellular matrix remodeling pathways, integrin-related signaling and cellular trafficking mediators indicating the contributions of Cep55 to cancer are beyond what have been reported so far. Overall, CEP55 is a promising target to prevent tumorigenesis and the progression of cancer through various mechanisms. Citation Format: Behnam Rashidieh, Simon M. Tria, Kum Kum Khanna. Understanding the role of Cep55 in initiation and progression of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6033.
Abstract CT035: Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer
Authors: Olivier Rixe, Vincent Castonguay, Henry Conter, Eva Chalas, Pratibha Desai, Christian Squillante, Lisa A. MacDonald, Rebekah Conlon, Yogesh Bramhecha, Heather Hirsch, Jeremy R. Graff, Stephan Fiset
Journal: Cancer Research (2022)

Abstract Background: Maveropepimut-S (MVP-S) is a novel immunotherapeutic that educates a specific CD8 T cell response to the cancer antigen, survivin, to orchestrate immune-mediated elimination of survivin-expressing cancer cells. Specifically, MVP-S is a lipid-in-oil formulation of the DPX delivery platform, incorporating five survivin-specific immunogenic peptides, the innate immune stimulant, polydIdC, and a CD4 T cell helper peptide. In prior clinical studies, MVP-S and intermittent low-dose cyclophosphamide (CPA) elicited confirmed clinical responses (both partial and complete by RECISTv1.1) and induced a robust, durable survivin-specific CD8 T cell response. Moreover, the combination with pembrolizumab appeared to be well tolerated in solid tumors and lymphomas. The purpose of this phase 2 study is to explore whether this combination may be safe and effective in advanced, metastatic bladder cancer patients, both naïve to, and previously treated with, immune checkpoint inhibitors. Results: Seventeen (17) subjects were treated with the combination of MVP-S, CPA and pembrolizumab. Subjects received an average of 3 prior lines of therapy with 13/17 (76.4%) having previously received an anti-PD1/L1. Seven subjects progressed on or after anti-PD1/L1 as last line of therapy prior to entering the trial. The combination was well-tolerated, with majority of AEs being grade 1 or grade 2. Five (5) out of 17 subjects showed response: 3 subjects with PR (unconfirmed) and 2 with CR (confirmed). Three of these, including the 2 CRs, had progressed on anti-PD-1/L1. Long-term clinical benefit has been observed in several subjects (one patient is still on treatment after 17 months) and coincides with an increase in detectable survivin-specific T cells in peripheral blood. Conclusion: Preliminary data suggest that MVP-S/CPA and pembrolizumab is a well-tolerated combination and shows encouraging preliminary clinical activity in the treatment of advanced or metastatic bladder cancer patients, including patients who have progressed on prior anti-PD-1/L1 therapy. Citation Format: Olivier Rixe, Vincent Castonguay, Henry Conter, Eva Chalas, Pratibha Desai, Christian Squillante, Lisa A. MacDonald, Rebekah Conlon, Yogesh Bramhecha, Heather Hirsch, Jeremy R. Graff, Stephan Fiset. Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT035.
Abstract 5486: ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment
Authors: Ying-ying Li, Zhiyuan Peng, Shuaijun Sun, Kun Guo, Deming Kong, Xiaomin Li, Yuning Xie, Siyu Shui, Yin Wang, Jinfu Yang, Xiaolin Alan Hao, Xiaoli (Shelley) Qin
Journal: Cancer Research (2022)

Abstract Emerging studies revealed that tumor derived 2’3’-cGAMP could act as an immune transmitter and directly trigger anti-tumor immunity. Damage associated molecular patterns, e.g. damaged genomic DNA, released from injured cancer cells can be converted into 2’, 3’-cGAMP by cGAS. Subsequently, cGAMP triggers STING pathway activation to produce type I interferons (IFNs) and other related innate immunity in the tumor microenvironment. Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a membrane-bound nucleotide hydrolase, has been discovered as the predominant enzyme hydrolyzing 2’3’-cGAMP (Li, et al). Hence, ENPP1 blockade in the tumor milieu is a potential strategy against tumors by improving innate immunity response. In this report, we present a potent ENPP1 inhibitor ZX-8177. ZX-8177 showed an IC50 of 9.5 nM in a biochemical assay and an IC50 of 11 nM in MDA-MB-231 cell-based enzymatic assay. In a functional assay for evaluating efficacy of ZX-8177, the production of IFN-β1 by THP-1 cells was measured after the cells were cultured in the conditioned medium collected from MDA-MB-231 cells treated with or without ZX-8177. The interferon production assay showed an EC50 of 15 pM, suggesting that ZX-8177 effectively facilitated IFN-β1 production via cGAMP-STING axis. In CT-26 syngeneic mouse model, ZX-8177 treatment at 2 mg/kg, BID for 14 days can achieve around 37-60% tumor growth inhibition (TGI). No body weight loss was observed during treatment. Flow cytometry analysis indicated that ZX-8177 treatment resulted in a 2-3-fold increase in tumor-infiltrating NK (CD314+CD335+) cells, cytotoxic CD8 T cells (GranzB+CD8+), and M1-macrophages (CD206-MHCII+); and a decrease in M2-macrophages (CD206+MHCII-) (p&amp;lt; 0.05). Combination of Mitomycin C (0.5 mg/kg, i.p., BIW) and ZX-8177 (2 mg/kg, i.p., BID) in CT-26 model yielded synergistic anti-tumor efficacy (increased &amp;gt;30% TGI). The level of cGAMP in tumor tissue harvested from the combination treatment group was around 2-fold higher than that in the vehicle group. Furthermore, synergistic tumor inhibition of ZX-8177 and anti-PD-L1 antibody was also observed in MC38 mouse model. TGI of anti-PD-L1 antibody vs. combo treatment is 53% vs. 75%, p &amp;lt; 0.05. ZX-8177 has a favorable DMPK and safety pharmacology profile to support it as a clinical candidate for further development. Citation Format: Ying-ying Li, Zhiyuan Peng, Shuaijun Sun, Kun Guo, Deming Kong, Xiaomin Li, Yuning Xie, Siyu Shui, Yin Wang, Jinfu Yang, Xiaolin Alan Hao, Xiaoli (Shelley) Qin. ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5486.
Abstract 1825: Romidepsin therapy results in p53 mediated apoptosis in hepatoblastoma
Authors: Andres F. Espinoza, Richard Whitlock, Rohit Srivastava, Roma Patel, Sai Govindu, Aayushi Shah, Samuel Larson, Sarah Woodfield, Sanjeev Vasudevan
Journal: Cancer Research (2022)

Abstract Purpose: Relapsed and treatment refractory hepatoblastoma (HB) has a survival rate less than 50% due to limited treatment options. We have previously shown that HB and treatment refractory HB has upregulation of class I histone deacetylase (HDAC) genes (HDAC1-4) through microarray, confirmed by RT-PCR. The highest consistent upregulation noted was with HDAC 2 and 3. Given this upregulation, we tested established and treatment refractory HB cell lines with HDAC 2/3 inhibitor, Romidepsin. We sought to characterize Romidepsin efficacy and mechanism of action. Methods: Romidepsin was tested with cytotoxic assays (MTT). Tumor derived cell lines were treated with Romidepsin and evaluated for gene expression of p53 pathway via qRT-PCR. Immunoblotting assays were used to assess changes in expression of Acetyl-p53 at time points of 0, 4, 8, and 24 hours after 0.01 µM concentrated Romidepsin treatment. Evaluation of the specific cell death pathway involved was performed via cell viability assays using 0.01 µM concentration of Romidepsin in combination with cell death reversal agents including Z-VAD for apoptosis, 3-Methyladenine for autophagy, Necrostatin-1 for necroptosis, and Ferrostatin-1 for ferroptosis at 48 hours. Results: Romidepsin (IC50 of 0.001-0.02 µM) showed strong in vitro effects for viability. HB cell lines treated with HDAC inhibitor had increased p21 and PUMA expression on RT-PCR, most notably at the 24-hour mark (p = &amp;lt; 0.05). Acetyl p-53 was noted to increase in HUH-6 and Hep G2 throughout the 24 hours of treatment on western blots, while Hep T1 was noted to have no changes in expression. All cell lines showed the highest level of cell death reversal with ZVAD in cell viability assay after Romidepsin treatment. Hep T1 showed the highest cell death reversal with Romidepsin: relative cell viability of 52% (±5%) versus 95% (±2%) in ZVAD/Romidepsin. Conclusions: Romidepsin demonstrates strong in vitro efficacy and suggest HDAC 2/3 inhibition may act through p53 mediated mechanism, notably acetylated p53. Cell death via apoptosis is further supported by cell death reversal with ZVAD/Romidepsin treatment in HB cell lines. Citation Format: Andres F. Espinoza, Richard Whitlock, Rohit Srivastava, Roma Patel, Sai Govindu, Aayushi Shah, Samuel Larson, Sarah Woodfield, Sanjeev Vasudevan. Romidepsin therapy results in p53 mediated apoptosis in hepatoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1825.
Abstract 1419: Single molecule detection of human heparanase
Authors: Zhishen Wang
Journal: Cancer Research (2022)

Abstract Heparanase, a mammalian endo-β-D-glucuronidase, is the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs). Its activity is implicated in various disease conditions such as tumor growth, angiogenesis, metastasis, chronic inflammation and diabetic nephropathy. Detecting the activity of heparanase thus is a promising approach for the discovery of diagnostics and therapeutics for these diseases. We have developed an activity-based disaccharide probe for heparanase, which offers over 700-fold of fluorescence increase in the presence of human heparanase. In this project, we aim to build up an ultrasensitive single heparanase detection system by coupling a sensitive fluorogenic probe with a microwell-based device. The microwell-based device is designed to achieve single enzyme separation and significantly increase the sensitivity of detection. This system is being validated using recombinant human heparanase and will be used to analyze clinical samples from breast cancer patients. Citation Format: Zhishen Wang. Single molecule detection of human heparanase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1419.
Abstract 2793: Minimal residual disease (MRD) as a predictive biomarker/endpoint for novel drug development
Authors: Nicholas Jones, Brian Ngo, Floyd Davis, Benjamin Fancke
Journal: Cancer Research (2022)

Abstract MRD is defined as the continual presence of cancer cells in patients post therapy that is below the threshold of detection by conventional morphologic or radiologic assessments. Monitoring patient status clinically as MRD negative or MRD positive has become the basis for predicting outcomes, remission or reoccurrence, as well as determining therapeutic options. The three primary methods to assess MRD status in patients include Flow Cytometry (FC), Polymerase Chain Reaction (PCR) and Next-Generation Sequencing (NGS). All three are highly quantitative measurements with a high degree of sensitivity to detect “new” circulating tumor cells or ctDNA that can potentially indicate disease recurrence before it happens. The choice of MRD methodology usually depends on the tumor type, liquid or solid. Flow Cytometry has been widely used to monitor MRD status in patients with hematologic malignancies. Specifically designed MRD panels have been used clinically in CLL, MM, CML and AML patients. In addition to its prognostic/diagnostic relevance, recent guidance by the FDA is now driving the use of MRD testing as a predictive biomarker/endpoint for novel cancer drug development. NeoGenomics Pharma Services has provided flow cytometry MRD expertise to multiple sponsors conducting clinical trials to evaluate the effectiveness of novel cancer therapy. In a CLL study, NeoGenomics employed the ERIC MRD assessment to monitor patient status during therapeutic intervention at various points throughout treatment. Representative patient data show progression from full, active disease prior to therapy to non-detectable disease levels below 0.01%MRD. These examples show patient progression through multiple cycles of treatment to full remission. Clearly, this is an example of how MRD can serve as the primary “biomarker” to evaluate a patient’s response to novel drug therapy in clinical trials. This presentation will further discuss the data and the relevance of MRD testing to support new drug development. Citation Format: Nicholas Jones, Brian Ngo, Floyd Davis, Benjamin Fancke. Minimal residual disease (MRD) as a predictive biomarker/endpoint for novel drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2793.
Abstract 667: Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response
Authors: Seung Bum Park, Wansang Cho, Won Sol Chan, young il choi, Sungoh Ahn, Dong-Sup Lee
Journal: Cancer Research (2022)

Abstract Introduction: STimulator of INterferon Genes (STING) has been reported to be essential for antitumor immunity by inducing type I IFN expression, resulting in activation of both innate and adaptive immunity. Thus, pharmacological activation of STING pathway is actively being tested in many clinical studies. However, the clinical efficacy was not that clear, probably due to the limited expression of STING protein, which is tightly regulated by TRIM29 (E3 ligase)-mediated protein degradation pathway. Here, we present a novel small-molecule drug candidate with strong antitumor response in murine syngeneic model by upregulating cellular levels of STING through the inhibition of protein-protein interaction. Methods: The inhibitors of STING-TRIM29 interaction were identified using luciferase-complementation high-throughput screening system. Target protein of the inhibitor was identified in cellular thermostability shift assay. Their immunological activity was tested in Raw264.7 and A431 cells as well as CT26 murine syngeneic model. Results: The lead compound, SB24011, bound to STING and upregulated cellular levels of STING by inhibiting ubiquitin-mediated degradation. Together with STING agonist, SB24011 synergistically enhanced the inflammatory cytokine expression in cell lines as well as in CT26 syngeneic animal model. Intratumoral injection of SB24011 showed strong abscopal activity as single agent as well as synergistic antitumor responses with anti-PD1 antibody in CT26 syngeneic animal model. Conclusions: We identified novel small-molecule drug candidate, SB24011, which prevents the degradation of both murine and human STING proteins, resulting in enhanced immune responses together with STING agonist, cGAMP. SB24011 showed strong abscopal antitumor activity as single agent and synergistic antitumor activity as combination agent with other IO agents in CT26 syngeneic models. Citation Format: Seung Bum Park, Wansang Cho, Won Sol Chan, young il choi, Sungoh Ahn, Dong-Sup Lee. Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 667.